We have applied high peak airway pressure (50 cm H2O) positive pressure ventilation to healthy anesthetized and sedated sheep while monitoring changes in total static lung compliance (TSLC), functional residual capacity (FRC), and arterial blood gases. Following some 12-48 hours of continuous mechanical ventilation, there was marked reduction in TSLC, FRC, and a severe deterioration in arterial blood gases. One group of animals was then randomized to a state of the art mechanical pulmonary ventilation management group, with best efforts made to wean to room air. All but one animal so managed died of progressive respiratory failure. In the remaining animals, high pressure mechanical pulmonary ventilation was discontinued and they were placed on continuous positive airway pressure (CPAP), and on an extracorporeal membrane lung perfusion system. Following some 24 hours of such treatment, all but one animal showed progressive improvement in arterial blood gases, and in lung function, and could be weaned from bypass. We believe mechanical pulmonary ventilation at elevated peak airway pressures is a major cause of clinical morbidity and mortality. The novel application of the extracorporeal perfusion system with the membrane artificial lung is likely to find rapid clinical application.